Objective We examined the Grp78, ERK1/2 and phospho-ERK1/2 expressions in hepatocellular carcinoma(HCC) tissue samples EM>in vitro/EM>, we interfered the expression of Grp78 in SMMC-7721 cells to explore whether Grp78 is involved in ERK1/2 signal pathway. Methods The Grp78, ERK1/2 and phospho-ERK1/2 expressions were detected by immunohistochemistry and confirmed by Western blotting in 47 HCC tissue samples. The Grp78 expression in SMMC-7721 cells was interfered by plasmid transfection and siRNA, ERK1/2 phosphorylation and expression were determined by Western blotting. Results The Grp78 expression was significantly correlated with ERK1/2 and phospho-ERK1/2 in HCC tissue samples. Overexpression of Grp78 promoted ERK1/2 phosphorylation in SMMC-7721 cells and the increased ERK1/2 phosphorylation was inhibited by Grp78 knockdown. Conclusion Grp78 is involved in the regulation of ERK1/2 signal pathway and might be a potential target for the comprehensive therapy of HCC.